Immunophilins and related proteins participate in many fundamental biological processes, and this project's overall goal is analyzing these processes in structural terms. In addition to providing a basic structural understanding of these important proteins, the project has practical implications for prevent graft versus. host disease in transplant patients, alleviating autoimmune diseases such as rheumatoid arthritis and insulin- dependent diabetes, and developing small molecules for regulated gene therapy. Separate projects include: Structures of the large immunophilins FKBP51 and FKB952 along with their partners in the steroid receptor complex Hip and Hop. Structure of FRAP, a member of the ATM family of proteins involved in cell cycle checkpoints and DNA repair. Structure of dihydroorotate dehydrogenase, the protein target of the rheumatoid arthritis drug leflunomide (Arava) and the anti- cancer agent brequinar. Structure of the dimerizing agents based on FKBP12-rapamycin- FRB that are clinically useful in small molecule regulated gene therapy. Structures such as fyn SH2-pYEEI/FK506-FKBP52 that illustrate the concept of using borrowed endogenous proteins to moderate the binding of hybrid small molecules.